Candidate: I obtained my Ph.D in Biomedical Engineering. My post-doc training focused on clinical investigations of changes in bone microstructure that affect bone strength and fracture risk in osteopenia, osteoporosis, and other metabolic bone diseases. My long-term goal is to develop as an independent research investigator able to combine the fields of bone imaging and biomechanics with bone cell and molecular biology. Thus, my specific objective here is to obtain training in cell and molecular biology and in vivo animal models in order to uncover and clarify the overall mechanisms behind PTH-induced, modeling-based bone formation. By combining my expertise in innovative imaging and image analyses with cellular, molecular and in vivo animal approaches, the proposed research project promises to represent a major new first attempt to understand the direct modeling component of PTH's anabolic action at the local level. Mentor and Advisory Committee: The primary Mentor Dr. Louis Soslowsky, an international leader in mechanical adaptation of musculoskeletal tissue, will serve as my mentor for both career development and scientific content. The co-Mentor Dr. Maurizio Pacifici, a world-renowned scientist in skeletal development and growth, will serve as scientific mentor. The advisory committee consists of Dr. Xu Cao at the Johns Hopkins University, who will advise on bone modeling and remodeling; Dr. Paola Divieti Pajevic at the Harvard Medical School, who will advise on PTH receptor and osteocyte signaling; and Dr. Ling Qin at my local institution, who will provide hands-on training in cellular and molecular experiment skills. Environment: The research/training environment at Penn includes 15,500 ft2 of shared lab space in the McKay Orthopaedic Research Laboratory; multiple shared experimental facilities, including an in vivo and a specimen micro computed tomography (CT) scanner, histology core facilities, equipment for cellular and molecular biology, and mechanical testing core facilities; numerous vivarium facilities available to investigators for both conventional and barrier housing options; numerous seminars and lecturers, and career development courses. Training Plan: The training plan includes research training in the Mentors' and advisors' laboratories in techniques utilizing genetically-modified mouse models, and cell and molecular measurements using histology, biochemical assays, and immunohistochemistry. The training plan also includes courses in the molecular biology of aging, grant writing, career development, and responsible conduct of research; attendance at several seminar series pertinent to candidate's research training; journal clubs; and presentations at a minimum of 2 national conferences per year. Research: Current osteoporosis treatments aim to elicit an anti-catabolic or anabolic bone response. However, due to bone formation-resorption coupling mechanisms, drugs inhibiting bone resorption often inhibit formation, and those increasing formation also increase resorption, thereby limiting their potential benefits. In contrast, several studies including those we recently performed, suggest that pre-treatment with bisphosphonates followed by intermittent recombinant human parathyroid hormone 1-34 (iPTH) treatment may result in modeling-based bone formation, i.e., bone formation with minimal activation of resorption. Through this mechanism, a combination therapy of iPTH and anti-catabolic agents could activate bone formation with minimal concomitant bone resorption, thus eliciting an overall beneficial effect stronger than current mono- therapies. However, results from clinical trials have been highly variable. Controversies remain, due in part to unclear mechanisms of PTH's role in controlling modeling-based bone formation. Recent studies suggested that PTH acts on osteocytes to control the balance between resorption and formation through the regulation of Sost/sclerostin, RANKL and OPG in osteocytes. Interestingly, treatment with a sclerostin-neutralizing antibody was recently found to induce strong modeling-based bone formation. iPTH has been shown to down-regulate sclerostin production, leading to our central hypothesis that iPTH regulates modeling-based bone formation and does so partially by acting on osteocytes and influencing their signaling activity. According, Aim 1 is to characterize modeling-based bone formation on trabecular and cortical bone surfaces in response to iPTH in a young and old mouse model. We will exploit our novel 3D, CT-based, in vivo bone dynamic imaging approaches, combined with 2D histological methods, to allow characterization of modeling- and remodeling- based bone formation at individual sites with unparalleled sensitivity and accuracy. Aim 2 is to delineate the roles of the PTH receptor (PPR) in osteocytes and osteoblasts in iPTH-induced, modeling-based bone formation. Here we will determine whether this anabolic response requires expression of PPR in osteocytes or osteoblasts. Dmp1-CreER; PPRfl/fl and OCN-CreER; PPRfl/fl mice will be treated with tamoxifen to induce PPR deficiency in osteocytes and osteoblasts, respectively. Their responses to iPTH and combined iPTH and alendronate treatment will be evaluated. We anticipate that this investigation will shed light on more efficient therapeutic strategies for osteoporosis that favor formation over resorption. Institutional Commitment to the Candidate: The candidate holds a tenure-track faculty position at Penn, which has provided laboratory space, start-up funding, and support for graduate students and post-docs.